Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.3.99.3 (acyl-CoA dehydrogenase)
 1,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The beta-oxidation of valproic acid (2-propylpentanoic acid), an anticonvulsant drug with hepatotoxic side effects, was studied with subcellular fractions of rat liver and with purified enzymes of beta-oxidation. 2-Propyl-2-pentenoyl-CoA, a presumed intermediate in the beta-oxidation of valproic acid, was chemically synthesized and used to demonstrate that enoyl-CoA hydratase or crotonase catalyzes its hydration to 3-hydroxy-2-propylpentanoyl-CoA. The latter compound was not acted upon by soluble L-3-hydroxyacyl-CoA dehydrogenases from mitochondria or peroxisomes but was dehydrogenated by an NAD(+)-dependent dehydrogenase associated with a mitochondrial membrane fraction. The product of the dehydrogenation, presumably 3-keto-2-propylpentanoyl-CoA, was further characterized by fast bombardment mass spectrometry. 3-Keto-2-propylpentanoyl-CoA was not cleaved thiolytically by 3-ketoacyl-CoA thiolase or a mitochondrial extract but was slowly degraded, most likely by hydrolysis. The availability of 2-propylpentanoyl-CoA (valproyl-CoA) and its beta-oxidation metabolites facilitated a study of valproate metabolism in coupled rat liver mitochondria. Mitochondrial metabolites identified by high-performance liquid chromatography were 2-propylpentanoyl-CoA, 3-keto-2-propylpentanoyl-CoA, 2-propyl-2-pentenoyl- CoA, and trace amounts of 3-hydroxy-2-propylpentanoyl-CoA. It is concluded that valproic acid enters mitochondria where it is converted to 2-propylpentanoyl-CoA, dehydrogenated to 2-propyl-2-pentenoyl-CoA by 2-methyl-branched chain acyl-CoA dehydrogenase, and hydrated by enoyl-CoA hydratase to 3-hydroxy-2-propylpentanoyl-CoA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mitochondrial metabolism of valproic acid. 198 37

Respiration-linked oxidation of 3-hydroxybutyryl-CoA, crotonyl-CoA and saturated fatty acyl (C4, C8 and C14)-CoA esters was studied in different mitochondrial preparations. Oxidation of acyl-CoA esters was poor in intact mitochondria; however, it was significant, as well as, NAD+ and CoA-dependent in gently and in vigorously sonicated mitochondria. The respiration-linked oxidation of crotonyl-CoA and 3-hydroxybutyryl-CoA proceeded at much higher rates (over 700%) in gently disrupted mitochondria than in completely disrupted mitochondria. The redox dye-linked oxidation of crotonyl-CoA (with inhibited respiratory chain) was also higher in gently disrupted mitochondria (149%) than in disrupted ones. During the respiration-linked oxidation of 3-hydroxybutyryl-CoA the steady-state NADH concentrations in the reaction chamber were determined, and found to be 8 microM in gently sonicated and 15 microM in completely sonicated mitochondria in spite of the observation that the gently sonicated mitochondria oxidized the 3-hydroxybutyryl-CoA much faster than the completely sonicated mitochondria. The NAD(+)-dependence of 3-hydroxybutyryl-CoA oxidation showed that a much smaller NAD+ concentration was enough to half-saturate the reaction in gently disrupted mitochondria than in completely disrupted ones. Thus, these observations indicate the positive kinetic consequence of organization of beta-oxidation enzymes in situ. Respiration-linked oxidation of butyryl-, octanoyl- and palmitoyl-CoA was also studied and these CoA intermediates were oxidized at approx. 50% of the rate of crotonyl- and 3-hydroxybutyryl-CoA in the gently disrupted mitochondria. In vigorously disrupted mitochondria the oxidation rate of these saturated acyl-CoA intermediates was hardly detectable indicating that the connection between the acyl-CoA dehydrogenase and the respiratory chain had been disrupted.
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PMID:Kinetic advantage of the interaction between the fatty acid beta-oxidation enzymes and the complexes of the respiratory chain. 199 30

A case of severe hypoglycaemia precipitated by fasting in a child is described. As a result of the hypoglycaemia, the patient became brain damaged. The mechanism causing the hypoglycaemia was a defect in the fatty acid beta-oxidation enzyme, the connecting link acyl-CoA dehydrogenase. During a prolonged fast, fatty acids are not converted to acetyl-CoA and ketone bodies which participate in Kreb's cycle for production of energy to a sufficient extent. This result in non-ketotic hypoglycaemia with excretion of organic acids in the urine. As a rule, the symptoms occur for the first time during the first to second years of life in connection with common infectious diseases, with vomiting followed by clouding of consciousness and possibly coma, but the condition may also present with sudden unexpected death. Treatment consists of intravenous glucose. The diagnosis is established by testing the urine for hexanoylglycin and other substances and is confirmed by culture of skin fibroblasts and measurement of beta-oxidation activity. The disease is an autosomally recessive inherited condition. In families where there have been cases of unexplained hypoglycaemia and clouding of consciousness and cases of unexplained death in infancy or "near misses", all of the family members should be offered examination for the above mentioned enzyme deficiency.
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PMID:[Severe hypoglycemia and clouding of consciousness caused by deficiency of the connecting link acyl CoA dehydrogenase]. 200 Jun 54

Riboflavin-deficient rats are used to study the metabolism of deuterium-labeled nonanoic acids under conditions mimicking the human disorder of multiple acyl-CoA dehydrogenase deficiency in which large amounts of ethyl-malonic, glutaric, adipic, suberic, 4-octenedioic, sebacic and 4-decenedioic acids are excreted. Both control and deficient rats convert the nonanoic acids to labeled azelaic and pimelic acids. The labeling pattern in pimelic acid is consistent with the omega-oxidation of nonanoic acids to azelaic acid followed by beta-oxidation to pimelic acid.
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PMID:Metabolism of deuterium-labeled nonanoic acids in the riboflavin-deficient rat model of multiple acyl-CoA dehydrogenase deficiency. 205 91

Five distinct acyl-CoA dehydrogenases are currently known. These are short, medium, long and 2-methyl-branched-chain acyl-CoA dehydrogenases, and isovaleryl-CoA dehydrogenase. We tested these five acyl-CoA dehydrogenases for their ability to dehydrogenate valproyl-CoA using pure enzyme preparations isolated from rat liver mitochondria. The activities of the pure human short-chain, medium-chain and isovaleryl enzymes purified from post-mortem livers, and a long-chain acyl-CoA dehydrogenase preparation partially purified from placental mitochondria, were also tested. Valproyl-CoA was dehydrogenated at a significant rate (0.167 mumol/min per mg protein) only by rat 2-methyl-branched-chain acyl-CoA dehydrogenase. Human 2-methyl-branched-chain acyl-CoA dehydrogenase has not been purified; therefore, it could not be tested. Since four other human acyl-CoA dehydrogenases did not dehydrogenate isobutyryl-CoA, 2-methylbutyryl-CoA (obligatory intermediates from valine and isoleucine, respectively) nor valproyl-CoA, it is reasonable to assume that valproyl-CoA is dehydrogenated by 2-methyl-branch-chain acyl-CoA dehydrogenase in man as well. We identified 2-propyl-2-pentenoyl-CoA as the reaction product from valproyl-CoA by mass spectral analysis of the acyl moiety. Valproyl-CoA, at 0.3 mM, moderately inhibited human acyl-CoA dehydrogenases with the exception of the long-chain enzyme. 5 mM free valproic acid inhibited the activities of various acyl-CoA dehydrogenases only very weakly.
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PMID:The enzymatic basis for the metabolism and inhibitory effects of valproic acid: dehydrogenation of valproyl-CoA by 2-methyl-branched-chain acyl-CoA dehydrogenase. 211 56

Medium-chain acyl-CoA dehydrogenase reduced with octanoyl-CoA is reoxidized in two one-electron steps by two molecules of the physiological oxidant, electron transferring flavoprotein (ETF). The organometallic oxidant ferricenium hexafluorophosphate (Fc+PF6-) is an excellent alternative oxidant of the dehydrogenase and mimics a number of the features shown by ETF. Reoxidation of octanoyl-CoA-reduced enzyme (200 microM Fc+PF6- in 100 mM Hepes buffer, pH 7.6, 1 degree C) occurs in two one-electron steps with pseudo-first-order rate constants of 40 s-1 and about 200 s-1 for k1 and k2, respectively. The reaction is comparatively insensitive to ionic strength, and evidence of rate saturation is encountered at high ferricenium ion concentration. As observed with ETF, the free two-electron-reduced dehydrogenase is a much poorer kinetic reductant of Fc+PF6-, with rate constants of 3 s-1 and 0.3 s-1 (for k1 and k2, respectively) using 200 microM Fc+PF6-. In addition to the enoyl-CoA product formed during the dehydrogenation of octanoyl-CoA, binding a number of redox-inert acyl-CoA analogues (notably 3-thia- and 3-oxaoctanoyl-CoA) significantly accelerates electron transfer from the dehydrogenase to Fc+PF6-. Those ligands most effective at accelerating electron transfer favor deprotonation of reduced flavin species in the acyl-CoA dehydrogenase. Thus this rate enhancement may reflect the anticipated kinetic superiority of anionic flavin forms as reductants in outer-sphere electron-transfer processes. Evidence consistent with the presence of two distinct loci for redox communication with the bound flavin in the acyl-CoA dehydrogenase is presented.
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PMID:Alternate electron acceptors for medium-chain acyl-CoA dehydrogenase: use of ferricenium salts. 227 71

Plasma concentrations of valproate and certain of its metabolites and their patterns of excretion in urine are described in three adults who developed hepatotoxicity during treatment of epilepsy with sodium valproate. One patient also developed a degree of reversible renal insufficiency, whilst another may have had associated infectious mononucleosis. All three cases showed evidence of impaired mitochondrial beta-oxidation of valproate. In one the impairment was at the stage catalysed by fatty acyl-CoA dehydrogenase, in another at the stage catalysed by 3-hydroxyacyl-CoA dehydrogenase and in the third at the stage catalysed by enoyl-CoA hydratase and possibly also at the next stage catalysed by 3-hydroxyacyl-CoA dehydrogenase. The impaired beta-oxidation meant that valproate metabolism was diverted into various alternative pathways. Plasma concentrations of the suspected hepatotoxic metabolite 4-en-valproate were normal for the valproate-treated population in all cases. By analogy with certain spontaneous and acquired human disorders of branched chain amino acid metabolism, it is suggested that valproate-associated hepatotoxicity may represent the consequences of a valproate overload on a limited mitochondrial beta-oxidation capacity, causing accumulation of a toxic product of endogenous branched chain amino acid metabolism.
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PMID:Valproate metabolism during hepatotoxicity associated with the drug. 229 Sep 19

Inactivation of five distinct acyl-CoA dehydrogenases by (methylenecyclopropyl)acetyl-CoA (MCPA-CoA), the toxic metabolite of hypoglycin from unripe ackee fruit, was investigated using purified enzyme preparations. Short-chain acyl-CoA (SCADH), medium-chain acyl-CoA (MCADH) and isovaleryl-CoA (IVDH) dehydrogenases were severely and irreversibly inactivated by MCPA-CoA, while 2-methyl-branched chain acyl-CoA dehydrogenase (2-meBCADH) was only slowly and mildly inactivated. Long-chain acyl-CoA dehydrogenase (LCADH) was not significantly inactivated, even after prolonged incubation with MCPA-CoA. Inactivation of SCADH, MCADH and IVDH was effectively prevented by the addition of substrate. This mode of inactivation by MCPA-CoA explains the urinary metabolite profile in hypoglycin treated-rats, which includes large amounts of metabolites from fatty acids and leucine, and relatively small amounts of those from valine and isoleucine. Spectrophotometric titration of SCADH and MCADH with MCPA-CoA, together with the protective effects of substrate, indicates that MCPA-CoA is acted upon by, and exerts in turn irreversible inactivation of, SCADH and MCADH, confirming that MCPA-CoA is a suicide inhibitor (Wenz et al. (1981) J. Biol. Chem. 256, 9809-9812). Spectrophotometric titration data of LCADH and MCPA-CoA is typical of non-reacting CoA ester.
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PMID:Selective inactivation of various acyl-CoA dehydrogenases by (methylenecyclopropyl)acetyl-CoA. 233 85

Studies of the spectral (UV/vis and resonance Raman) and electrochemical properties of the FAD-containing enzyme glutaryl-CoA dehydrogenase (GCD) from Paracoccus denitrificans reveal that the properties of the oxidized enzyme (GCDox) appear to be invariant from those properties known for other acyl-CoA dehydrogenases such as mammalian general acyl-CoA dehydrogenase (GACD) and butyryl-CoA dehydrogenase (BCD) from Megasphaera elsdenii. However, when either free or complexed GCD is reduced, its spectral and electrochemical behavior differs from that of both GACD and BCD. Free GCD does not stabilize any form of one-electron-reduced GCD, but when GCD is complexed to its inhibitor, aceto-acetyl-CoA, the enzyme stabilizes 20% of the blue neutral radical form of FAD (FADH.) upon reduction. Like GACD, when crotonyl-CoA- (CCoA) bound GCD is reduced, the red anionic form of FAD radical (FAD.-) is stabilized, and excess reduction equivalents are necessary to effect full reduction of the complex. A comproportionation reaction is proposed between fully reduced crotonyl-CoA-bound GCD (GCD2e-CCoA) and GCDox-CCoA to partially explain the stabilization of GCD-bound FAD.- by CCoA. When GCD is reduced by its optimal substrate, glutaryl-CoA, a two-electron reduction is observed with concomitant formation of a long-wavelength charge-transfer band. It is proposed that the ETF specific for GCD abstracts one electron from this charge-transfer species and this is followed by the decarboxylation of the oxidized substrate. At pH 6.4, potential values measured for free GCD and GCD bound to acetoacetyl-CoA are -0.085 and -0.129 V, respectively. Experimental evidence is given for a positive shift in the reduction potential of GCD when the enzyme is bound to a 1:1 mixture of butyryl-CoA and CCoA. However, significant GCD hydratase activity is observed, preventing quantitation of the potential shift.
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PMID:Spectral and electrochemical properties of glutaryl-CoA dehydrogenase from Paracoccus denitrificans. 234 Feb 66

Significant thermodynamic changes have been observed for general acyl-CoA dehydrogenase (GAD) upon substrate binding. Spectroelectrochemical studies of GAD and several of its substrates have revealed that these substrates are essentially isopotential for chain lengths of C-4 to C-16 (E 0' =-0.038 to -0.045 V vs SHE). When GAD is bound by these substrates, a dramatic shift in the midpoint potential of the enzyme is observed (E 0' = -0.136 V for ligand-free GAD and -0.026 V for acyl-CoA-bound GAD), thus allowing a thermodynamically favorable transfer of electrons from substrate to enzyme. This contrasts with values reported elsewhere. From these data an isopotential scheme of electron delivery into the electron-transport chain is proposed.
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PMID:Regulation of the redox potential of general acyl-CoA dehydrogenase by substrate binding. 234 Feb 67


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